Defining the Mechanism of Alpha-synuclein Dependent Restriction of Viral Neuroinvasion

α-突触核蛋白(-syn)是一种神经元特异性蛋白，可导致帕金森氏症。蛋白质总是 表达的和最近的工作表明，在外周神经元中错误折叠成纤维。 胃肠道轨迹和嗅球。这些纤维随后在SELECT中扩散到中枢神经系统 导致帕金森氏病或弥漫性路易体痴呆等神经退行性疾病的个人。 随着退伍军人年龄的增长和工作时间的延长，他们面临患神经退行性疾病的风险 了解帕金森氏病的病因将产生治疗和防止神经退行性变的新方法 疾病。我们已经发现，病毒感染会启动SYN的翻译后修改，这些修改是 与帕金森氏症有关。此外，我们先前的工作已经表明，syn具有抑制病毒的功能。 从周围神经扩散到中枢神经系统的感染。 综上所述，我们的发现揭示了对SYN在大脑中的作用的惊人的新理解。我们 假设病毒感染诱导SYN的翻译后修饰作为一种抗病毒机制。 虽然这种反应具有强烈的保护性，但暴露于这种环境中会增加Synn诱导的病理的风险，从而 导致帕金森氏症中发现的长期神经退行性疾病。我们将评估我们的假设 通过明确-SYN诱导的神经元抑制西尼罗河病毒感染的机制及其相互作用 在SYN翻译后修饰和α-SYN原纤维扩散之间。我们将利用分子科学中的技术 病毒学结合帕金森研究领域中已建立的小鼠模型来定义 SYN与脑内病毒感染之间的特定相互作用及其后果。如果 建议的研究完成后，我们将提供新的数据，将对 帕金森氏病研究和神经病毒学领域。因此，我们提议的工作将有显著的好处。 通过改善健康和提供潜在的预防和治疗新方法，为我们的退伍军人群体提供 像帕金森氏症这样的神经退化过程。

Alpha-synuclein (syn) is a neuron-specific protein known to cause Parkinson’s disease. The protein is always expressed and recent work has shown that syn mis-folds into fibrils in peripheral neurons in the gastrointestinal track and the olfactory bulb. These fibrils then spread to the central nervous system in select individuals resulting in neurodegenerative diseases like Parkinson’s disease or Diffuse Lewy Body Dementia. Veteran populations are at risk for developing neurodegenerative diseases as they age and work to understand the cause of Parkinson’s disease will yield new approaches to treat and prevent neurodegenerative diseases. We have discovered that virus infections initiate post-translational modifications of syn that are associated with Parkinson’s disease. Moreover, our prior work has shown that syn functions to inhibit virus infections from spreading from the peripheral nerves to the central nervous system. Taken together, our findings reveal a stunning new understanding of the role of syn in the brain. We hypothesize that viral infections induce post-translational modifications in syn as an antiviral mechanism. While this response is acutely protective, exposure increases the risk of syn-induced pathology that can result in long term neurodegenerative diseases found in Parkinson’s disease. We will evaluate our hypothesis by defining the mechanism of syn-induced inhibition of WNV infection in neurons and defining the interactions between syn post-translational modifications and α-syn fibril spread. We will utilize techniques in molecular virology in combination with established mouse models in the field of Parkinson’s research to define the specific interactions and consequences of the interactions between syn and viral infection in the brain. If the proposed studies are completed as outlined, we will provide novel data that will have significant impact on the field of Parkinson’s disease research and neurovirology. Thus, our proposed work will have significant benefits for our veteran populations by improving health and providing potential new approaches to prevent and treat neurodegenerative processes like Parkinson’s disease.